Defining total-body AIDS-virus burden with implications for curative strategies

Area of Science:

• Virology
• Immunology
• Infectious Diseases

Background:

• Effective HIV eradication strategies require understanding viral reservoirs responsible for infection rebound after treatment cessation.
• Lymphoid tissues (LTs) are critical sites for persistent HIV infection and viral rebound.

Purpose of the Study:

• To quantify Simian Immunodeficiency Virus (SIV) and Human Immunodeficiency Virus (HIV) tissue burdens in infected nonhuman primates and human lymphoid tissue biopsies.
• To assess the impact of antiretroviral therapy (ART) on viral reservoirs and identify sources of viral rebound.

Main Methods:

• Quantification of SIV and HIV RNA+ and DNA+ cells in tissue samples from infected nonhuman primates and humans.
• Analysis of viral load and drug concentrations in lymphoid tissues and peripheral blood during ART.
• Estimation of residual tissue viral DNA burden and potential for replication-competent proviruses.

Main Results:

• Before ART, LTs harbored >98% of SIV RNA+ and DNA+ cells.
• ART significantly reduced viral RNA+ cells, but they remained detectable in LTs, associated with lower drug concentrations compared to peripheral blood.
• Prolonged ART decreased SIV/HIV-DNA+ cells, yet an estimated 10^8 vDNA+ cells persisted, indicating significant reservoirs and ongoing virus production in LTs, contributing to rebound post-treatment.

Conclusions:

• Substantial reservoirs of replication-competent HIV exist in lymphoid tissues, even after prolonged ART.
• The persistence of viral reservoirs and ongoing virus production in LTs are major obstacles to achieving a functional HIV cure.
• Targeting multiple virus production sources is crucial for developing effective HIV cure strategies.